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Chemists shorten the synthesis of molnupiravir to prepare for scale-up

The antiviral drug candidate is in advanced clinical trials for fighting SARS-CoV-2 infection

by Bethany Halford
January 2, 2021 | A version of this story appeared in Volume 99, Issue 1


Structure of molnupiravir.

Chemists have developed an environmentally friendly route for making the investigational antiviral compound molnupiravir from commodity chemicals in just three steps with 69% overall yield. They reported the work on the preprint server ChemRxiv (2020, DOI: 10.26434/chemrxiv.13472373.v1), and it has not yet been peer-reviewed.

Molnupiravir, previously known as EIDD-2801, kills SARS-CoV-2 in cells and is currently in Phase 2/3 clinical trials to test its effectiveness at fighting COVID-19 in people. To date, Gilead Sciences’ Veklury (remdesivir) is the only antiviral that has received approval from the US Food and Drug Administration for treating COVID-19, but it must be given intravenously. Molnupiravir can be taken in pill form, so it could be given as an outpatient treatment, if approved.

In May 2020, Merck & Co. announced a collaboration with Ridgeback Biotherapeutics to develop molnupiravir. At that time, the reported route for making the compound took 10 steps, starting with a 4-step conversion of ribose to uridine. The overall yield of the process was less than 10%.

Chemists led by Merck’s Patrick S. Fier developed a faster route. With the help of an enyzme, they convert ribose’s primary alcohol into an isobutyl ester. They then use a novel biocatalytic cascade reaction to install uracil at the appropriate position on the sugar. Finally, they selectively convert one of the uracil moiety’s carbonyls to an oxime, creating molnupiravir. The new, three-step route, the researchers say, should make it easier to make large supplies of the compound if it is approved.



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